11{62 -methyl-17{60 -propadienyl steroids

ABSTRACT

11 Beta -methyl-17 Alpha -propadienyl substituted steroids, e.g., 17 Beta -hydroxy-11 Beta -methyl-17 Alpha propadienylestra-4-en-3-one, are prepared by reducing the corresponding 11 Beta -methyl-17 Alpha -quaternary amino-propynyl steroid salt and are useful as progestationals in fertility control.

United States Patent Coombs 1 Mar. 27, 1973 l1B-METHYL-l7a-PROPADIENYL STEROIDS Inventor: Robert V. Coombs. Summit, NJ.

Ave., Summit, NJ.

Field of Search ..Machine Searched Steroids References Cited UNITED STATES PATENTS 7/1968 Edwards et al. ..260/239.55

3,325,520 6/1967 Baran ..260/397.45 3,377,366 4/1968 Baran ...260/397.45 3,465,010 9/1969 Baran ..260/397.5

Primary ExaminerHenry A. French Att0rney-Gerald D. Sharkin, Frederick H. Weinfeldt, Robert S. Honor, Walter F. Jewell and Richard E. Vila [57] ABSTRACT llB-methyl-l7a-propadienyl substituted steroids, e.g., l7B-hydroxy-l lfi-methyl- 1 7a-propadienylestra-4-en- 3-one, are prepared by reducing the corresponding l1B-methyl-l7a-quatemary amino-propynyl steroid salt and are useful as progestationals in fertility control.

7 Claims, N0 Drawings llfi-METHYL-l7a-PROPADIENYL STEROIDS This invention relates to llB-mcthyl-l7a-propadienyl-4 or 5(10)-en-steroid, intermediates for their preparation and their use in fertility control.

The compound of this invention may be represented by the formula where R isunbranched lower alkyl, i.e., unbranched lower alkyl having one to three carbon atoms; namely, methyl, ethyl or propyl; and

(All) The compounds of formula I are prepared in accordancewith the following reaction scheme:

. where R and A are as defined above.

The compound of formula I in which ring A is of the A type are prepared by the acid cleavage-rearrangement of compounds of formula 11, under vigorous acidic conditions. The vigorous acidic conditions may consist of carrying out the reaction either in a strongly acidic aqueous medium, i.e., at a pH value of less than 3 and preferably from I to 2 or alternatively, under milder acidic conditions, for example, at a pH value of from 3 to 4, over a relatively prolonged'period, for example, in excess of 3 hours. Conventional water soluble inorganic or organic acids, e.g., sulphuric acid, ptoluene sulfonic acid, hydrochloric acid or oxalic acid may be used to provide the strongly acidic conditions; and water soluble organic acid, e.g., oxalic acid or acetic acid, may be used to provide the milder acidic conditions. The particular acid used in the reaction is not critical.

The process may be carried out at temperatures of from, for example, 0 to 100 C. preferably from 20 to 70 C. An inert water-miscible organic co-solvent,

preferably a lower alcohol such as methanol may be used where desired and where a water-soluble organic acid, suitable as a solvent under the reaction conditions, is employed, the reaction may be carried out in an excess thereof. Neither the temperature nor the parverted to its analog having an A type A-ring by vigorous acidic-rearrangement, that is, by employing the vigorous conditions described above, except that aqueous conditions are not essential, nor need the solvent be water-miscible. The vigorous conditions may involve either the treatment of the compound with the A" type A-ring with acid at a pH of less than 3 or treatment of the compound with acid at a pH between 3 and 4 over a period in excess of 3 hours.

Alternatively, the rearrangement from the A to the A type A-ring may be carried out in a basic medium, for example, employing aqueous sodium or potassium hydroxide, preferably at a concentration of from about 0.01N to about 2N. The basic rearrangement may be affected in an inert organic solvent such as dioxane, methanol or ethanol. It is preferred that the solvent of the rearrangement process be water-miscible. The reaction may be performed at a temperature of, for example, 20 to C., preferablyat the reflux temperature of the reaction medium. Suitable reaction times vary, for example, from about one-fourth hour to about 6 hours.

In the above processes, the product is recovered by conventional techniques, e.g., extraction and evaporation.

The compounds of formula II are novel and represent an additional aspectof this invention and are prepared in accordance with the following reaction where R is as defined above.

The compounds of formula II are prepared by reducing a compound of formula III with a complex metal hydride in an inert solvent. The complex metal hydride can be any of the conventional complex metal hydrides, preferably lithium aluminum hydride or sodium dimethoxyethoxy aluminum hydride. The inert solvent may be any of the inert aliphatic or aromatic solvents or ethers, preferably benzene, diethyl ether or tetrahydrofuran. Although the temperature is not critical, the reaction is generally carried out at temperatures between 80 C. to +80 C., preferably between 10 C. to +10 C. Neither the particular complex metal hydride used not the solvent employed is critical. The product is recovered by conventional techniques, e.g., extraction and evaporation.

The compounds of formula III are novel and represent an additional aspect of this invention and are prepared in accordance with the following reaction scheme:

where R is as defined above.

The compound of formula III is prepared by treating a compound of formula IV with methyl iodide V. Although a solvent is not necessary, it is preferred that the reaction be carried out in an inert solvent, preferably acetone. The temperature of the reaction is not critical, although it is preferred that the reaction be carried out at a temperature of from about 20 C. to +30 C., especially between about C. to about +l0 C. The product is obtained by conventional methods, e.g., crystallization and filtration.

The compounds of formula IV are novel and represent an additional aspect of this invention and are prepared in accordance with the following reaction scheme:

on3 A H CH (VII) II CH 0 where R is as defined above.

The compounds of formula IV are prepared by treating a compound of formula VI with N,N- dimethylamino-2-propynyllithium in an inert solvent. The preferred inert solvents are diethyl ether or tetrahydrofuran. Where the N,N-dimethylamino-2- propynyllithium is prepared in situ in ethylenediamine, the ethylenediamine can be used as a co-solvent in the reaction. Although the temperature of the reaction is not critical, it is preferred that the process be carried out at temperatures between about C. to +50 C. especially between about 20 C. to about +30 C. The product is obtained by conventional methods, e.g., by the addition of water or brine followed by extraction with ether and recrystallization.

The compounds V and VII and many of the compounds of formula VI are known and can be prepared by methods disclosed in the literature. The compounds of formula VI not specifically disclosed in the prior art 30 can be prepared by analogous methods from known materials.

Compounds I are useful because they possess pharmacological properties in animals. In particular, such compounds are useful as fertility control agents in animals as they exhibit progestational activity. The progestational activity is indicated by the well known Clauberg test; the method basically described in Endocrinology 63 (I958) 464 wherein a rabbit is given 001 to 1.0 milligrams of active agent.

These compounds may be combined with a pharmaceutically acceptable carrier or adjuvant. They may be administered orally or parenterally. The dosage will vary depending upon the mode of administration utilized and the particular compound employed. However, in general, satisfactory results are obtained in large animals, e.g., primates when the compounds are administered at a daily dosage of from about 0.01 milligram to 30 milligrams. This daily dosage is preferably given in equally divided doses, e.g., 1 to 2 times a day, or in sustained release form. It will be appreciated by those skilled in the art, that the daily dosage level is independent of body weight. Dosage forms suitable for internal administration comprise from about 0.005 mg. to about 30 mg. of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

A representative formulation suitable for oral administration is a capsule (250 mg.) prepared by standard techniques which contains the following:

Ingredient l7B-hydorxy-I lB-methyll 7a-propadienylestra-4- en-3-one Inert solid diluent (starch, lactose, kaoline) Weight (mg.)

EXAMPLE 1 17B-hydroxy-1 IB-methyl- 1 7a-propadienylestra-4-en 3-one CH3 I ()II Step A 3-methoxy-l 1B-methyl-17a-N,N- dimethylaminopropynylestra-2,5(10)-dien-17B-o1 A total of 1.8 g of lithium is added in small portions to 120 ml of ethylene diamine with stirring at a temperature of 50 60 under nitrogen. After addition is complete, the blue solution is heated at 75 85 for 1 lhours whereat a pale yellow reaction mixture is obtained. This mixture is then cooled to 10, and g of N,N-dimethylamino-2-propyne is added dropwise over 5 minutes. Stirring is continued at room temperature for 1 hour, at which point a solution of 2.6 g of 3- methoxy-l1B-methylestra-2,5(l0)-dien-17-one in 40 ml of tetrahydrofuran is added. The mixture is now stirred at room temperature for 4 hours; and after cooling in an ice-water mixture, 100 ml of brine are added under nitrogen followed by 250 ml of ether. The two layers are separated, and the aqueous layer is extracted 3 times with benzene. The combined organic phases are washed with brine and dried over sodium sulfate.

After removal of the solvents, the residue is crystallized from ether to yield 3-methoxy-l 1B-methyl-17a-N,N- dimethylaminopropynylestra-2,5( 10 )-dien-1 73-01 (m.p. 17o-175 Step B 3-methoxy-11B-methyl-17a-N,N- dimethylaminopropynylestra-2,5( 10 )-dien-1 73-01 methiodide To a solution of 2.5 g of 3-methoxy-l lB-methyl-17a- N,N- dimethylaminopropynylestra-Z,S(10)-dien-17B-ol in 60 ml of acetone is added 15 ml of methyl iodide.

The solution is kept at a temperature of 5 for 18 hours during which time a crystalline precipitate forms. This is filtered off and recrystallized from acetone to yield 3- methoxy- 1 1B-methyl-17a-N ,N- dimethylaminopropyny1estra-2,5( lO)-dien-17B-o1 methiodide, m.p. 255-260 (decomposition).

Step C 3-methoxy-1lB-methyl-l'Za-propadienylestra-2,5( 10)-dien-l 713-01.

To a suspension of 3.1 g of the iodide salt from Step I B in 100 ml of anhydrous tetrahydrofuran, under ice 6 y-l IB-methyl-l7a-propadieny1estra-2,5(10)-dien-17B- ol, m.p. 135. Step D 17B-hydroxy-1 lB-methyl-17apropadeinylestra-5(10)-en-3-one A suspension of 1 g of 3-methoxy-l1B-methyl-l7apropadienylestra-2,5( l0)-dien-17B-diol in a mixture of 20 ml of glacial acetic acid and 2.5 ml of water is stirred at room temperature for l zfihours at which time solution is complete. The solution is diluted with ice/water and saturated aqueous sodium bicarbonate is cautiously added until the mixture is no longer acidic. The mixture is then extracted with ether and the organic solution is dried over sodium sulfate. Evaporation of the ether yields a residue which is crystallized from ether/hexane (1:2) to give 17B-hydroxy-llB-methyll7a-propadienylestra-5(10)-en-3-one, m.p. 104 105.

When the procedure of Step D is repeated and the reaction is run for 6 hours instead'of l rhours, the product obtained is 17B-hydroxy-11fl-methyl-17apropadienylestra-4-en-3-one.

Step E 17B-hydroxy1 lB-methyl-17apropadienylestra-4-en-3-one To a solution of 800 mg of 3-methoxy-l lB-methyll7a-propadienylestra-2,5(l0)-dien-17fl-ol in 10 ml of methanol is added 5 drops of concentrated hydrochloric acid and the mixture is left at room temperature for 1 %hours. The mixture is then diluted with ice/water and a saturated aqueous solution of sodium bicarbonate is cautiously added until the mixture is no longer acidic. The solution is then extracted with ether, and the organic phase after separation is dried over sodium sulfate. Evaporation of the solvent yields a residue which is crystallized from ether/hexane, (1:2) to give 17 B-hydroxy-l lfi-methyl-l7a-propadienylestra-4-en-3-one, m.p. 137- 139.

Step F l7B-hydroxy-1 1B-methyl-17apropadienylestra-4-en-3-one (alternate method A) Replacing the 3-methoxy-1 1B-methyl-17apropadienylestra-2,5(10)-dien-l7B-ol in Step E by 17B-hydroxy-1 IB-methyl-l7a-propadienyl-5(10)-en-3 -one prepared by the procedure of Step D and following the procedure of Step E, there is obtained 17B- hydroxy-l IB-methyl-l 7a-propadienylestra-4-en-3- one, m.p. 137- 139.

Step G 17B-hydroxy-1 lfimethyl-Uapropadieny1estra-4-en-3-one (alternate method B) To a solution of 1.0 g of 17 B-hydroxy-l IB-methyl- 17a-propadienylestra-5(10)-en-3-one prepared as described in Step D of this example in 10 ml of methanol is added 10 ml of aqueous 0.1N potassium hydroxide and the resulting mixture is refluxed for 1 hour. Following this, the mixture is poured on water and the resulting precipitate is filtered, washed with water until neutral and then dried. Recrystallization from methylene dichloride-diethyl ether yields 17B- hydroxy-l 1 B-methyl-l 7a-propadienylestra-4-en-3- one, m.p. l37139. I

Following the procedures of Steps A through D, but substituting 3-methoxy-1 3B-ethyl-1 lB-methylgono-2,5 (l0)-dien-17-one for the 3-methoxy-1lB-methylestra- 2,5(10)-dien-17-one used in Step A, there is obtained l7B-hydroxy-l3B-ethyl-1 lfi-methyl-17a propadienylgona-5( l0)-en-3-one.

When l7B-hydroxy-13B-ethyl-l lB-methyl-17apropadineylgona-5(l0)-en-3-one is used in place of 3- methoxy-l IB-methyl-l7a-propadienylestra-2,5( l)- 0 dien-l7B-ol in the process of Step E, there is obtained /k l7B-hydroxyl 3B-ethyl-l lB-methyll 7a-propadienylf 1h H CH:

gona-4-en-3-one.

What is claimed is: l. A compound of the formula OH R |----CH=C=CH2 CHEO CH; where R is as defined in claim 1.

5. The compound of claim 4 which is 3-methoxy-l 1B -methyl- 1 7a-N ,N-dimethylamino-propynylestra-2,5

A (l0)-dien-17B-ol. 0 l5 quaternary ammonium salt of the formula where OH A V V R -CECCHzNCHa 1- v WA f CHa or q and 0- 0 CHaO R is unbranched lower alkyl. where 2. The compound of claim 1 which is l7B-hydroxy- 5 R is as d fi d in claim 1 l l y 'P P y '3' 7. The compound of claim 6 which is 3-methoxy-l 1B The compound of claim 1 which is fi' y y' -methyl-l7a-N,N-dimethyl-aminopropynylestra-2,5 l lB-methyl-l 7a-propadienylestra-5( l0)-en-3-one. 10 i 7 hi di 4. A compound ofthe formula i 

2. The compound of claim 1 which is 17 Beta -hydroxy-11 Beta -methyl-17 Alpha -propadienylestra-4-en-3-one.
 3. The compound of claim 1 which is 17 Beta -hydroxy-11 Beta -methyl-17 Alpha -propadienylestra-5(10)-en-3-one.
 4. A compound of the formula
 5. The compound of claim 4 which is 3-methoxy-11 Beta -methyl-17 Alpha -N,N-dimethylamino-propynylestra-2,5(10)-dien-17 Beta -ol.
 6. A quaternary ammonium salt of the formula
 7. The compound of claim 6 which is 3-methoxy-11 Beta -methyl-17 Alpha -N,N-dimethyl-aminopropynylestra-2,5(10)-dien-17 Beta -ol -methiodide. 